The proposed research is concerned with investigation of the mechanism of selective toxicity of cancer chemotherapeutic agents. The compounds to be studied initially will be F-pyrimidines, arabinosylcytosine, 6-mercaptopurine, 6-thioguanine, N6-isopentenyladenosine and N6-benzyladenosine. The objectives of this work are: 1) to quantitatively and qualitatively determine the concentration of purine and pyrimidine ribonucleoside and ribonucleotide pool sizes in human and animal tumors and in serum; 2) to evaluate the relative role of the "salvage" and de novo pathways in tumors and normal tissues; 3) to establish a relationship between the uptake and metabolism of the selected agents, and responsiveness in individual tumors; 4) to assay for key enzymes that are involved in the utilization of preformed ribonucleosides; and 5) to subclassify tumors according to the above parameters studied in an attempt to offer a prediction of their responsiveness to a given treatment. Much of the work in this proposal will be carried out in vivo using both mouse and rat tumors. Particular methods to be used involve high pressure liquid chromatography for the simultaneous analytical separation and identification of nucleosides and nucleotides, as well as DEAE-cellulose column chromatography for preparative purposes. The studies proposed herein should aid in the understanding of the biochemical basis for selective action of certain antimetabolites in individual tumors in vivo, and thus should provide a rationale for the design of specific chemotherapy with available drugs and metabolites, alone or in combination.